Impaired Insulin Secretion And Decreased Expression Of The Nutritionally Responsive Ribosomal Kinase Protein S6k-1 In Pancreatic Islets From Malnourished Rats

Low protein diet has been shown to affect the levels and activities of several enzymes from pancreatic islets. To further extend the knowledge on how malnutrition affects insulin secretion pathway, we investigated in this work the insulin release induced by glucose or leucine, an insulin secretagogue, and the expression of insulin receptor (IR), insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K), and p70S6K1 (S6K-1) proteins from pancreatic islets of rats fed a normal (17%; NP) or a low (6%; LP) protein diet for 8 weeks. Isolated islets were incubated for 1 h in Krebs-bicarbonate solution containing 16.7 mmol/L of glucose, or 2.8 mmol/L of glucose in the presence or absence of 20 mmol/L of leucine. Glucose- and leucine-induced insulin secretions were higher in NP than in LP islets. Western blotting analysis showed an increase in the expression of IR and PI3K protein levels whereas IRS1 and S6K-1 protein expression were lower in LP compared to NP islets. In addition, S6K-1 mRNA expression was also reduced in islets from LP rats. Our data indicate that a low protein diet modulates the levels of several proteins involved in the insulin secretion pathway. 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Increased L-cpt-1 Activity And Altered Gene Expression In Pancreatic Islets Of Malnourished Adult Rats: A Possible Relationship Between Elevated Free Fatty Acid Levels And Impaired Insulin Secretion

Intrauterine growth restriction is associated with chronically elevated levels of serum fatty acids and reduced glucose-stimulated insulin secretion. Lipid metabolism in pancreatic β cells is critical for the regulation of insulin secretion, and the chronic exposure to fatty acids results in higher palmitate oxidation rates and an altered insulin response to glucose. Using a rat model of isocaloric protein restriction, we examined whether pre- and postnatal protein malnutrition influences the properties of pancreatic islet carnitine palmitoyltransferase-1 (liver isoform, L-CPT-1), a rate-limiting enzyme that regulates fatty acid oxidation in mitochondria. The activity of L-CPT-1 in pancreatic islets increased in the low protein (LP), although the L-CPT-1 mRNA levels were unaffected by malnutrition. The susceptibility of enzyme to inhibition by malonyl-CoA was unaltered and the content of malonyl-CoA was reduced in LP cells. Because the mitochondrial oxidation of fatty acids is related to the altered expression of a number of genes encoding proteins involved in insulin secretion, the levels of expression of insulin and GLUT-2 mRNA were assessed. A reduced expression of both genes was observed in malnourished rats. 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Decreased Cholinergic Stimulation Of Insulin Secretion By Islets From Rats Fed A Low Protein Diet Is Associated With Reduced Protein Kinase Cα Expression

Undernutrition has been shown to affect the autonomic nervous system, leading to permanent alterations in insulin secretion. To understand these interactions better, we investigated the effects of carbamylcholine (CCh) and phorbol 12-myristate 13-acetate (PMA) on insulin secretion in pancreatic islets from rats fed a normal (17%; NP) or low (6%; LP) protein diet for 8 wk. Isolated islets were incubated for 1 h in Krebs-bicarbonate solution containing 8.3 mmol glucose/L, with or without PMA (400 nmol/L) and CCh. Increasing concentrations of CCh (0.1-1000 μmol/L) dose dependently increased insulin secretion by islets from both groups of rats. However, insulin secretion by islets from rats fed the NP diet was significantly higher than that of rats fed the LP diet, and the dose-response curve to CCh was shifted to the right in islets from rats fed LP with a 50% effective concentration (EC50) of 2.15 ± 0.7 and 4.64 ± 0.1 μmol CCh/L in islets of rats fed NP and LP diets, respectively (P < 0.05). PMA-induced insulin secretion was higher in islets of rats fed NP compared with those fed LP. Western blotting revealed that the protein kinase (PK)Cα and phospholipase (PL)Cβ1 contents of islets of rats fed LP were 30% lower than those of islets of rats fed NP (P < 0.05). In addition, PKCα mRNA expression was reduced by 50% in islets from rats fed LP. In conclusion, a reduced expression of PKCα and PLCβ1, may be involved in the decreased insulin secretion by islets from LP rats after stimulation with CCh and PMA.1333695699Becker, D.J., The endocrine responses to protein calorie malnutrition (1983) Annu. Rev. 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Low-protein Diets Reduce Pkaα Expression In Islets From Pregnant Rats

We investigated the effect of protein restriction on insulin secretion and the expression of protein kinase (PK)Aα and PKCα in islets from control and pregnant rats. Adult control nonpregnant (CN) and control pregnant (CP) rats were fed a normal-protein diet (17%), whereas low-protein nonpregnant (LPN) and low-protein pregnant (LPP) rats were fed a low-protein diet (6%) for 15 d. In the presence of 2.8 and 8.3 mmol glucose/L, insulin secretion by islets of CP rats was higher than that by islets of CN rats. Compared with the CN groups, insulin secretion by islets of LPN rats was lower with 8.3 but not with 2.8 mmol glucose/L. The insulin secretion by islets of LPP rats was higher than by LPN rats at both glucose concentrations. IBMX (1 mmol/L), a phosphodiesterase inhibitor, increased insulin secretion by islets from pregnant rats, and this effect was greater in islets of CP rats than in LPP rats. Forskolin (0.01-100 μmol/L), a stimulator of adenylyl cyclase, increased insulin secretion only in islets of CN and CP rats, with a higher 50% effective concentration in islets of CP rats compared with CN rats. The insulin secretion induced by phorbol 12-myristate 13-acetate (a stimulator of PKC) was higher in islets of LPN and LPP rats than in the respective controls, especially at 8.3 mmol glucose/L. PKAα, but not PKCα, expression was lower in islets of rats fed low protein than in the controls, regardless of the physiological status of the rats. All endocrine cells of the islets, including β-cells, expressed the PKAα isoform. The cytoplasmic distribution of this enzyme in β-cells was not modified by pregnancy and/or protein restriction. In conclusion, our results indicate that the response of islets from rats fed low protein during pregnancy is similar to that of control rats, at least for physiologic glucose concentration. However, the decreased response to IBMX and forskolin indicates decreased production and/or sensitivity to cAMP; this was associated with a decrease in PKA expression, which may result in lower PKA activity. © 2005 American Society for Nutritional Sciences.135818731878Carneiro, E.M., Mello, M.A.R., Gobatto, C.A., Boschero, A.C., Low protein diet impairs glucose-induced insulin secretion from and 45Ca uptake by pancreatic rats islets (1995) J. Nutr. Biochem., 6, pp. 314-318Ferreira, F., Filiputti, E., Arantes, V.C., Stoppiglia, L.F., Araujo, E.P., Delghingaro-Augusto, V., Latorraoa, M.Q., Carneiro, E.M., Decreased cholinergic stimulation of insulin secretion by islets from rats fed a low protein diet is associated with reduced protein kinase Ca expression (2003) J. 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Protein Restriction In Early Life Is Associated With Changes In Insulin Sensitivity And Pancreatic β-cell Function During Pregnancy

Malnutrition in early life impairs glucose-stimulated insulin secretion in adulthood. Conversely, pregnancy is associated with a significant increase in glucose-stimulated insulin secretion under conditions of normoglycaemia. A failure in β-cell adaptive changes may contribute to the onset of diabetes. Thus, glucose homeostasis and β-cell function were evaluated in control-fed pregnant (CP) and non-pregnant (CNP) or protein-restricted pregnant (LPP) and non-pregnant (LPNP) rats, from fetal to adult life, and in protein-restricted rats that were recovered after weaning (RP and RNP). The typical insulin resistance of pregnancy was not observed in the RP rats, nor did pregnancy increase the insulin content/islet in the LPP group. The glucose dose-response curves from pregnant rats were shifted to the left in relation to the non-pregnant rats, except in the recovered group. Glucose utilisation but not oxidation in islets from the RP and LPP groups was reduced at a concentration of 8·3Â mm-glucose compared with islets from the CP group. Cyclic AMP content and the potentiation of glucose-stimulated insulin secretion by isobutylmethylxanthine at a concentration of 2·8Â mm-glucose indicated increased adenylyl cyclase 3 activity but reduced protein kinase A-α activity in islets from the RP and LPP rats. Protein kinase C (PKC)-α but not phospholipase C (PLC)-β1 expression was reduced in islets from the RP group. Phorbol-12-myristate 13-acetate produced a less potent stimulation of glucose-stimulated insulin secretion in the RP group. Thus, the alterations exhibited by islets from the LPP group appeared to be due to reduced islet mass and/or insulin biosynthesis. In the RP group the loss of the adaptive capacity apparently resulted from uncoupling between glucose metabolism and the amplifying signals of the secretory process, as well as a severe attenuation of the PLC/PKC pathway. 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